Human Genome Project

30 Mar

Human Genome Project

orders usually do not run in families because their effects are so detrimental or lethal. They affect about seven individuals per thousand births and account for about half of all spontaneous first-trimester abortions. Polygenic disorders are determined by combined action of a number of genetic loci, each with a small effect. Single-gene disorders are cataloged in two online da- tabases. See GeneCards, OMIM. Human Genome Project a successful effort by an international coalition of scientists to complete the sequence and assembly of the human genome. Eval- uating the evolution and functioning of these genes is currently under way.

Once groups led indepen- dently by Francis Collins and J. Craig Venter fin- ished a draft sequence of the genome, a celebration was held on June 26, 2000, in the East Room of the White House. In his opening remarks President Clinton praised the draft saying “without a doubt, this is the most wondrous map ever produced by mankind.” By mid-February of 2001, annotated maps were published in Nature and Science, and The International Human Genome Sequencing Consor- tium published the completed sequence in 2003. See Appendix C, 2001, Collins and Venter et al.; 2003, International Human Genome Sequencing Consor- tium; Celera Genomics, DNA sequencers, shotgun se- quencing. human growth hormone (hGH) a protein (also called somatotropin) secreted by cells located in the anterior lobe of the pituitary gland. The hGH mole- cule folds upon itself and is held together by two disulfide bridges. There are two other hormones that have structures similar to hGH.

The first is chorionic somatomammotropin (hCS). Both hGH and hCS contain 191 amino acids, and hCS has two disulfide bridges in the same positions as hGH. There is an 85% identity between the amino acid sequences of hGH and hCS. The second hormone is prolactin (hPRL). It contains 199 amino acids, and the se- quence identities are lower (35% with hGH and 13% with hCS). The hypothalamus (q.v.) produces two hormones that modulate the secretion of hGH. Secretion is promoted by a 44 amino acid poly- peptide named growth hormone releasing hormone (GHRH), and secretion is inhibited by a 14 amino acid polypeptide named growth hormone inhibiting factor (GHIF). GHRH and GHIF are also called so- matocrinin and somatostatin, respectively. Limita- tions upon the supplies of hGH extracted from ca- davers restricted its clinical use in the treatment of pituitary dwarfism (q.v.).

These problems were overcome with the advent of recombinant DNA- derived hGH. See Appendix C, 1979, Goeddel et al., human growth hormone receptor. human growth hormone gene a gene located at 17q21. All primates contain five tandemly linked genes of similar structure. In humans, the sequence is 5′-GH1-CSHP1-CHS1-GH2-CSH2-3′. GH1 codes for the hGH secreted by the pituitary gland. The other four genes are expressed in the placenta. GH2 is a pseudogene (q.v.), which codes for an inactive form of hGH that differs from normal hGH by 13 amino acids. GSH1 and CSH2 encode hCS, and CSHP1 encodes a variant form of hCS. Each of the five genes contains five exons, which are interrupted at identical positions by small introns. All have simi- lar promotors and poly-A addition sites. The five genes presumably evolved from duplications of a common ancestral gene, followed by codon muta- tions.

See hereditary growth hormone deficiency, pi- tuitary dwarfism. human growth hormone receptor (hGHR) a re- ceptor protein that is activated on binding with growth hormone (GH) to stimulate the growth and metabolism of muscle, bone, and cartilage cells. The extracellular domains of two receptor proteins bind one molecule of GH. The hGHR protein is encoded by a gene in region 12-13.1 on the short arm of chromosome 5. Mutations in these genes cause La- ron dwarfism, a hereditary form of ateliosis inherited as an autosomal recessive. human immunodeficiency virus See AIDS, HIV. human mitochondrial DNA the mt chromosome is a circular DNA molecule that contains 16,560 bp. The genome is extremely compact. Coding se- quences make up 93% of the total genome, and all genes lack introns.

There are 37 genes; 28 are en- coded by the heavy strand and 9 by the light. There are 2 rRNA genes, 22 tRNA genes, and 13 genes that encode proteins, which function as subunits in enzymes that synthesize ATP. The original DNA se- quence published in 1981 is referred to as the Cam- bridge reference sequence. It contains errors that were corrected in 1999. After single base pair corrections were made at 10 sites, the revised Cambridge refer- ence sequence corresponds to European haplogroup H. See Appendix C, 1979, Barrell, Banker, and Drouin; 1981, Andrews et al.; ATP synthase, mito- chondrial DNA (mtDNA), mitochondrial syndromes, mitochondrion, mtDNA lineages. human mitotic chromosomes the number of hu- man chromosomes observed at mitosis was incor- rectly reported as 24 pairs by W. Flemming in 1898. It was not until 1956 that the correct number was determined as 23 pairs by J. H. Tjio and A. Levan. The mitotic chromosomes are generally grouped

Hunchback (hb)
into seven classes (A-G) according to the following cytological criteria: Group A (chromosomes 1-3) large chromosomes with approximately median cen- tromeres. Group B (chromosomes 4-5)—large chro- mosomes with submedian centromeres. Group C (chromosomes 6-12 and the X chromosome)—me- dium-sized chromosomes with submedian centro- meres. Group D (chromosomes 13-15)—medium- sized acrocentric chromosomes. Chromosome 13 has a prominent satellite on the short arm. Chromo- some 14 has a small satellite on the short arm. Group E (chromosomes 16-18)—rather short chro- mosomes with approximately median (in chromo- some 16) or submedian centromeres. Group F (chromosomes 19 and 20)—short chromosomes with approximately median centromeres. Group G (chromosomes 21, 22, and the Y chromosome)— very short acrocentric chromosomes.

See Appendix C, 1956, Tjio and Levan; 1971, O’Riordan; 1981, Harper and Saunders; 1991, Ijdo et al.; high-resolu- tion chromosome studies, human chromosome band designations, symbols used in human cytogenetics. human papilloma virus (HPV) a nonenveloped vi- rus with a genome of 8kb of ds DNA contained in an icosahedral capsid 55 nm in diameter. The ge- nome is divisible into an early (E) region, a late (L) region, and a C region. The E region contains 4 kb of DNA, the L region 3kb, and the C region about 1kb. The L genes encode the two proteins of the capsid, and the C segment is a noncoding control region. The genes of the E region function during viral replication. There are over 200 different strains of HPVs.

Most cause localized benign warts, but a few induce basal cells in the mucosa of the cervix to undergo uncontrolled proliferation. The potential to induce cervical cancer depends upon the genome of the specific viral strain. HPV carcinogenesis requires the integration of viral genomes into human chro- mosomes. It is the subsequent expression of E genes in the host cells that causes their transformation. E proteins modify the progression through the cell cy- cle, telomeres malfunction, and chromosomes segre- gate improperly, leading to aneuploidy. human pseudoautosomal region segments con- taining 2.5 Mbp of DNA in the distal parts of the short arms of the human X and Y chromosomes that share homologous genes.

These segments pair during meiosis, and obligatory crossing over takes place, so that genes in this region segregate like autosomal loci, rather than showing X or Y linkage. The gene MIC2 (q.v.) resides in this region. In the mouse, the steroid sulfatase gene (Sts) is pseudo-autosomal. The obligatory crossing over that occurs in the pseudoau- tosomal regions ensures that the X and Y chromo- somes will segregate properly at the first meiotic di- vision. See XG. human X chromosome the larger of the two sex chromosomes in humans. Females are XX; males XY. The X is composed of 155 mbp of DNA. It contains 1,098 genes, but only the 54 residing in the human pseudoautosomal region (q.v.) have alleles on the Y. In the somatic cells of females, one of the two X chromosomes is inactivated.

In the inacti- vated X, 75% of the genes are transcriptionally si- lenced, but 15% escape inactivation. The other 10% vary in their activity from one woman to another. See Appendix C, 2005, Ross et al.; dosase compensa- tion, sex determination, X chromosome inactivation. human Y chromosome the homolog of the X chromosome in males. The majority of the Y chromo- some never undergoes crossing over with the X. Crossing over only occurs within a pairing segment at the distal end of the short arm (Yp), called the human pseudoautosomal region (q.v.).

There is a similar pseu- doautosomal pairing segment on the X chromosome. The region of the Y that never undergoes crossing over is called the male specific region (MSY), and it comprises 95% of the chromosome’s length. Hetero- chromatin (q.v.) occupies the distal 2/3 of the long arm (Yq). Euchromatin (q.v.) comprises 23 mbp of DNA (8 mbp in Yp and 15 mbp in Yq).

Genes in the euchromatin encode about 30 different proteins or protein families. About half of these genes are ex- pressed predominantly or exclusively in the testis and half are expressed ubiquitously. See Appendix C, 2003, Skaletsky et al.; gene conversion, palin- drome, SRY, TSPY genes, XXY trisomic. humoral immunity immunoglobulin (antibody)- mediated immune responses.

humulin the trade name for a human insulin made in E. coli utilizing recombinant DNA techniques and marketed by Eli Lilly and Company. See Appendix C, 1982, Eli Lilly. hunchback (hb) a Drosophila gene located at 3- 48.3. It produces both maternal and zygotic tran- scripts, and these are translated into zinc finger pro- teins (q.v.) that regulate the transcription of other genes, especially those involved in the development of the head and thoracic segments of the embryo. The expression of hb is stimulated by a transcription factor encoded by bicoid (q.v.). Within the embryo this factor exists in a gradient where the concentra- tion is highest anteriorly and then trails off. The pos- terior expression of hb is controlled by a gene called nanos (q.v.). This encodes a translation repressor

Huntington disease (HD)

that is localized in the posterior pole of the em- bryo. See Appendix C, 1989, Driever and Nusslein- Volhard; zygotic segmentation mutants. Huntington disease (HD) a human neurological disease characterized by irregular, spasmotic, invol- untary movements of the limbs and facial muscles, mental deterioration, and death, usually within 20 years of the onset of symptoms. This neuropathy is named after George Huntington, the American phy- sician who published the first detailed account of the disorder in 1872. HD is an autosomal dominant dis- order with complete penetrance.

Symptoms do not usually appear until the victim is between 35 and 40 years of age. The HD gene is on chromosome 4 at p16.3. It generates a 10-kilobase transcript that en- codes huntingtin, a protein of unknown function. The mutation occurs in a polymorphic CAG repeat at the 5′ end of the gene. The CAG repeat is unsta- ble and is expanded in HD patients. The age of on- set is inversely correlated with repeat length.

The CAG repeats are translated into polyglutamine tracts, and the polyglutimine repeat sequences in mutant huntington molecules make them aggregate. Caspases (q.v.) cleave these mutant proteins and generate fragments that also contain polyglutamine tracts. These activate other caspases and so create a caspase cascade, ending in the death of brain cells. Genes homologous to human HD have been identi- fied in the mouse and the puffer fish. The Takifugu HD gene spans only 23 kb of genomic DNA, com- pared to the 170 kb human gene, and yet all 67 ex- ons are conserved. These exons are similar in size in puffer fish and humans, but the introns are much smaller in Fugu. In this fish the introns range in size from 47 to 1,476 bp, compared to human intron sizes of 131 to 12,286 bp. See Appendix C, 1979, Wexler et al.; 1993, MacDonald; 1995, Baxendale et al.; genetic instability, parental imprinting, Takifugu rubripes, trinucleotide repeats.

Hutchinson-Gilford syndrome a hereditary form of progeria (q.v.) described by the physicians Jona- than Hutchinson and Hastings Gilford in 1886 and 1897, respectively. HVL half-value layer (q.v.). Hyalophora cecropia the giant cecropia moth; be- cause of its large size a favorite experimental insect.

See Appendix C, 1966, Roller et al. hyaloplasm cytosol. hyaluronic acid a mucopolysaccharide that is abun- dant in the jelly coats of eggs and in the ground sub- stance of connective tissue. As shown below, hyal- uronic acid is a polymer composed of glucosamine and glucuronic acid subunits. hyaluronidase an enzyme that digests hyaluronic acid.

H-Y antigen an antigen detected by cell-mediated and humoral responses of homogametic individuals against heterogametic individuals of the same spe- cies, which are otherwise genetically identical. Anti- genic responses of this sort have been demonstrated in mammals, birds, and amphibians. In mammals, the antigen is called H-Y because it acts as a Histo- compatibility factor determined by the Y chromo- some. The location of the gene encoding the H-Y antigen is not known. However, the gene that in- duces synthesis of the H-Y antigen in humans is lo- cated on the Y chromosome.

A homologous locus, which suppresses H-Y production, lies on the distal end of the short arm of the X. The H-Y locus is one of the areas that escapes X-chromosome inactivation (q.v.). hybrid 1. a heterozygote (e.g., a monohybrid is heterozygous at a single locus: a dihybrid is hetero- zygous at two loci; etc.). 2. an offspring from geneti-
Hyaluronic acid

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